Wound healing is a complex biological process involving extracellular matrix, blood cells, parenchymal cells, and mediators such as cytokines. After the wound reaches hemostasis, the point where bleeding stops, the healing process begins. It occurs in three stages: inflammation, tissue formation (proliferation), and tissue regeneration (remodeling). Healing begins very quickly after injury occurs; for example, re-epithelialization of cutaneous wounds begins within hours (Singer and Clark, New Eng. J. Med. 341(10): 738-746 (1999)). The process of wound healing is initiated by myelinated afferent sensory nerves which in turn mediate neurogenic inflammation, immunological responses (Eglezos et al., Adv. Exp. Biol. Med. 273: 499-503 (1989); Immunol. Cell Biol. 69: 285-294 (1991)) and vascular tone (Khalil & Helme, Brain Res. 500: 256-262 (1989); Brain Res. 527: 292-298 (1990)), which are all essential components of healing. After the initiation of healing by sensory nerves, the process of healing is regulated by growth factors and cytokines that affect cell migration, proliferation, and protein production. In hemostasis, proteins such as fibrin and fibronectin interact to clot the blood, and cytokines and growth factors are upregulated. After injury, inflammation begins.
Inflammatory responses occur in three distinct phases, each apparently mediated by different mechanisms: (1) an acute transient phase, characterized by local vasodilatation and increased capillary permeability; (2) a delayed, subacute phase, most prominently characterized by infiltration of leukocytes and phagocyte cells; and (3) a chronic proliferative phase, in which tissue degeneration and fibrosis occur. Many different mechanisms are involved in the inflammatory process. The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury, although in some situations and diseases the inflammatory response may be exaggerated and sustained for no apparent beneficial reason. During inflammation, neutrophilis (polymorphonuclear leukocytes, PMNs), monocytes and macrophages infiltrate the wound. These phagocytic cells release growth factors for the proliferative phase, enzymatic mediators (proteases) that degrade proteins, and phagocytose bacteria, dead and dying cells thus debriding the wound.
In the next phase, proliferation begins. Collagen is deposited, forming scar tissue. Fibroblasts produce proteoglycans, which bind the collagen fibers together. Over time, the collagen is degraded by proteases and remodeled into a stronger scar structure.
Spinosyns (also known as A83453 factors) are agricultural, livestock and companion animal pesticides that have shown activity against 1) insects in the order Lepidoptera, 2) members of the order Homoptera, 3) members of the insect order Diptera, 4) members of the order Coleoptera, and 5) members of the order Anoplura. Formulations suitable for agricultural, livestock and companion animal administration include various suspensions, solutions, tablets, capsules, liquids and treats.
Spinosad (a product comprised primarily of spinosyn A, 85%, and spinosyn D, 15%) is currently approved in Australia and New Zealand for the treatment of lice on sheep and the treatment and prevention of blowfly strike on sheep. In Brazil, spinosad is approved for the topical treatment and control of certain ticks, flies and lice and as an antiseptic and cicatrizing repellent for treatment of botfly myiasis and skin wounds in cattle, sheep, goats, horses, pigs, birds and dogs.
Spinosyns are known to be useful for controlling lice infestations in a human, U.S. Pat. No. 6,063,771 and EP 1 252 820. Formulations suitable for such pediculicidal use in humans are also described in those patents.
Despite what is known regarding the ectoparasiticidal activity of the spinosyns and the commercial approvals, it has now been discovered that a spinosyn or a physiologically acceptable derivative or salt thereof has wound healing activity independently from a formulation containing an antiseptic/disinfectant agent.